Gata6+ Pericardial Cavity Macrophages Relocate to the Injured Heart and Prevent Cardiac Fibrosis

Deniset, Justin; Belke, Darrell D.; Lee, Woo Yong; Jorch, Selina K.; Deppermann, Carsten; Hassanabad, Ali Fatehi; Turnbull, Jeffrey; Teng, Guoqi; Rozich, Isaiah; Hudspeth, Kelly; Kanno, Yuka; Brooks, Stephen R.; Hadjantonakis, Anna‐Katerina; O’Shea, John J.; Weber, Georg F.; Fedak, Paul W.M.; Kubes, Paul

doi:10.1016/j.immuni.2019.06.010

Cited by 113 publications

(132 citation statements)

References 27 publications

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“…Aside from identifying peritoneal LpM as a source of macrophages in endometriosis lesions, these findings are important because they show that LpM are able to re-programme and survive in ectopic tissue, a topic of significant controversy in the field of 345 tissue-resident macrophage biology 38,39 . Indeed, our results are consistent with the reversible expression of GATA6 by LpM in the absence of sustained retinoic acid receptor signalling 11 and mirror recent findings that pericardial cavity GATA6+ macrophages lose expression of GATA6 following recruitment to areas of ischemic heart disease 40 . In the same manner, mature F4/80 hi GATA6+ peritoneal LpM are reported to traffic directly across the 350 mesothelium into the liver following sterile injury.…”

Section: Discussionsupporting

confidence: 92%

“…Our data suggest that in endometriosis LpM trafficking to lesions may play a similar role, perceiving the ectopic tissue as a wound and activating repair 355 processes. Interestingly, GATA6 positive macrophages that invade the epicardium from the pericardial space following experimental myocardial infarction were anti-fibrotic, despite a rapid loss of GATA6 expression 40 . Fibrosis is a consistent feature of endometriotic lesions 42 .…”

Section: Discussionmentioning

confidence: 99%

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Macrophages inhibit and enhance endometriosis depending on their origin

Hogg

Dhami

Rosser

et al. 2020

Preprint

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Macrophages are intimately involved in the pathophysiology of endometriosis, a chronic inflammatory disorder characterized by the growth of endometrial-like tissue (lesions) outside the uterus. By combining genetic and pharmacological monocyte and macrophage depletion strategies we determined the ontogeny and function of macrophages in a mouse 5 model of induced endometriosis. We demonstrate that lesion-resident macrophages are derived from eutopic endometrial tissue, infiltrating large peritoneal macrophages (LpM) and monocytes. Furthermore, we found endometriosis to trigger continuous recruitment of monocytes and expansion of CCR2+ LpM. Depletion of eutopic endometrial macrophages results in smaller endometriosis lesions, whereas constitutive inhibition of monocyte 10 recruitment significantly reduces peritoneal macrophage populations and increased the number of lesions. We propose a putative model whereby endometrial macrophages are pro-endometriosis whilst newly-recruited monocyte-derived macrophages, possibly in LpM form, are 'anti-endometriosis'. These observations highlight the importance of monocytederived macrophages in limiting disease progression. 15 20 25 30

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Macrophages inhibit and enhance endometriosis depending on their origin

Hogg

Dhami

Rosser

et al. 2020

Preprint

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“…Recent reports proposed that pericardial macrophages relocate to the epicardium and have protective properties, inhibiting interstitial fibrosis and preventing cardiac rupture (44), (45).…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomic profiling maps monocyte/macrophage transitions after myocardial infarction in mice

Rizzo

Vafadarnejad

Arampatzi

et al. 2020

Preprint

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RationaleMonocytes and macrophages have a critical and dual role in post-ischemic cardiac repair, as they can foster both tissue healing and damage. To decipher how monocytes/macrophages acquire heterogeneous functional phenotypes in the ischemic myocardium, we profiled the gene expression dynamics at the single-cell level in circulating and cardiac monocytes/macrophages following experimental myocardial infarction (MI) in mice. Methods and resultsUsing time-series single-cell transcriptome and cell surface epitope analysis of blood and cardiac monocytes/macrophages, as well as the integration of publicly available and independently generated single-cell RNA-seq data, we tracked the transitions in circulating and cardiac monocyte/macrophage states from homeostatic conditions up to 11 days after MI in mice. We show that MI induces marked and rapid transitions in the cardiac mononuclear phagocyte population, with almost complete disappearance of tissue resident macrophages 1 day after ischemia, and rapid infiltration of monocytes that locally acquire discrete and timedependent transcriptional states within 3 to 7 days. Ischemic injury induced a shift of circulating monocytes towards granulocyte-like transcriptional features (Chil3, Lcn2, Prtn3). Trajectory inference analysis indicated that while conversion to Ly6C low monocytes appears as the default fate of Ly6C hi monocytes in the blood, infiltrated monocytes acquired diverse gene expression signatures in the injured heart, notably transitioning to two main MI-associated macrophage populations characterized by MHCII hi and Trem2 hi Igf1 hi gene expression signatures. Minor ischemia-associated macrophage populations with discrete gene expression signature suggesting specialized functions in e.g. iron handling or lipid metabolism were also observed.We further identified putative transcriptional regulators and new cell surface markers of cardiac monocyte/macrophage states. ConclusionsAltogether, our work provides a comprehensive landscape of circulating and cardiac monocyte/macrophage states and their regulators after MI, and will help to further understand their contribution to post-myocardial infarction heart repair.

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“…Pathological context Contribution to fibrosis Neutrophils Ischemia 5 day post MI, increase in CD206 and or Arg-1 expressing neutrophils is associated with decreased myofibroblast transdifferentiation (Kain et al, 2018) 7 days post MI, neutrophils express Fibronectin, Gal-3, Fibrinogen which contributes to ECM reorganization (Daseke et al, 2019) 21 days post MI, loss of MPO reduces fibrosis (Mollenhauer et al, 2017) Post MI, loss of NGAL expressing neutrophils may affect dead myocyte phagocytosis and contribute to fibrosis (Horckmans et al, 2017) Myocarditis/DCM; Ageing In chronic myocarditis and ageing decreased neutrophil infiltration and NETosis/NET formation is associated with reduced fibrosis (Martinod et al, 2017;Weckbach et al, 2019) Monocytes/Macrophages Ischemia 1-6 weeks post MI, macrophages may transition to fibroblast-like cells, capable of secreting collagen (Haider et al, 2019) IL-10 and TGFβ secreting macrophages promote myofibroblasts transdifferentiation (O'Rourke et al, 2019) 1 week post ischemia/reperfusion, loss of MCP-1 is associated with decreased macrophage infiltration and interstitial fibrosis (Frangogiannis et al, 2007) 4 weeks post MI, Gata6 expressing pericardial macrophages limit cardiac fibrosis (Deniset et al, 2019) Pressure Overload Macrophage associated Gal-3 correlates with increased cardiac fibrosis in hypertensive rats (de Boer et al, 2009) 8 weeks following uninephrectomy and salty drinking water, loss of macrophage expressed mineralocorticoid receptor reduces cardiac collagen content (Rickard et al, 2009) Mast Cells Pressure Overload Mast cells contribute to PDGF-A expression and fibrosis in the heart following TAC (Liao et al, 2010) DCM Mast cells are a large source of FGF-2, and found within fibrotic sections of cardiac tissue (Bradding and Pejler, 2018) Eosinophils Myocarditis/DCM Eosinophil depletion post myocarditis is associated with decreased levels of MMP-2 and TIMP-2 (Diny et al, 2017) Dendritic Cells Ischemia Ablation of dendritic cells results in increased MMP-9 and MMP-2 activity 3-28 days post MI (Anzai et al, 2012) Pressure Overload Dendritic cell ablation following TAC is associated with decreased IL-1β and TGFβ and less fibrosis (Wang et al, 2017) Myocarditis/DCM BATF3 dependent dendritic cells limit cardiac fibrosis following viral infection (Clemente-Casares et al, 2017)…”

Section: Leukocyte Classmentioning

confidence: 99%

Leukocyte-Dependent Regulation of Cardiac Fibrosis

Okyere

Tilley

2020

Front. Physiol.

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Cardiac fibrosis begins as an intrinsic response to injury or ageing that functions to preserve the tissue from further damage. Fibrosis results from activated cardiac myofibroblasts, which secrete extracellular matrix (ECM) proteins in an effort to replace damaged tissue; however, excessive ECM deposition leads to pathological fibrotic remodeling. At this extent, fibrosis gravely disturbs myocardial compliance, and ultimately leads to adverse outcomes like heart failure with heightened mortality. As such, understanding the complexity behind fibrotic remodeling has been a focal point of cardiac research in recent years. Resident cardiac fibroblasts and activated myofibroblasts have been proven integral to the fibrotic response; however, several findings point to additional cell types that may contribute to the development of pathological fibrosis. For one, leukocytes expand in number after injury and exhibit high plasticity, thus their distinct role(s) in cardiac fibrosis is an ongoing and controversial field of study. This review summarizes current findings, focusing on both direct and indirect leukocyte-mediated mechanisms of fibrosis, which may provide novel targeted strategies against fibrotic remodeling.

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Gata6+ Pericardial Cavity Macrophages Relocate to the Injured Heart and Prevent Cardiac Fibrosis

Cited by 113 publications

References 27 publications

Macrophages inhibit and enhance endometriosis depending on their origin

Macrophages inhibit and enhance endometriosis depending on their origin

Single-cell transcriptomic profiling maps monocyte/macrophage transitions after myocardial infarction in mice

Leukocyte-Dependent Regulation of Cardiac Fibrosis

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